Field of the Invention
The present invention relates to novel processes for the preparation of substituted pyridylmethylbenzamide derivatives of formula (I), in particular 2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]methyl}benzamide (Fluopicolide), and for the catalytic hydrogenation of substituted cyanopyridine derivatives, in particular 3-chloro-2-cyano-5-trifluoromethylpyridine [=Py-CN] to the corresponding substituted 2-methylaminopyridine derivatives, in particular 2-aminomethyl-3-chloro-5-trifluoromethylpyridine [=Py-methylamine] or salts thereof in the presence of metal catalysts such as in particular palladium catalysts, catalytic modifiers and acids.
Description of Related Art
Substituted pyridylmethylbenzamide derivatives of formula (I)
wherein    p is an integer equal to 1, 2, 3 or 4,    q is an integer equal to 1, 2, 3 or 4,    each substituent X is chosen, independently of the others, as being hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl with the proviso that at least one X is halogen,    Y is halogen,    are highly active against phytopathogenic fungi. Compounds of formula (I) are described in EP-B-1056723.
Substituted cyanopyridine derivatives, wherein the substitution is present on the pyridine ring, such as in particular 3-chloro-2-cyano-5-trifluoromethylpyridine are important intermediates for the preparation of Fluopicolide (2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]methyl}benzamide), a commercially available fungicide, according to formula (Ia) shown below

In general the catalytic hydrogenation of nitriles is well known in the literature and can be carried out with different catalysts under either acidic or basic condition (Nishimura in “Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis”, pp. 254-285, John Wiley and Sons, New York, 2001). It is also known that the catalytic hydrogenation of nitriles to the desired primary amines is usually accompanied by the formation of significant amounts of secondary and tertiary amines which contaminate the desired primary amine and makes the isolation very complicated, costly and inefficient and thus not suitable for being used on an industrial scale.
The production of fluopicolide via catalytic hydrogenation is described in WO-A 2002/16322.
WO-A 2002/16322 discloses concretely the catalytic hydrogenation of 3-chloro-2-cyano-5-trifluoromethylpyridine [Py-CN] into 2-aminomethyl-3chloro-5-trifluoromethylpyridine [=Py-methylamine] in the presence of a palladium catalyst on charcoal in a protic solvent being methanol. The method described in WO-A 2002/16322 has the drawback in that the yield of the hydrogenation reaction from [Py-CN] to [Py-methylamine] is low. Another difficulty with this process is the potential for catalyst deactivation by the large amount of side products formed which could amount up to 5% of the end product. Side products include but are not limited to dechlorinated compounds, in particular of 2-[5-(trifluoromethyl)pyridin-2-yl]methanamine. In addition, the reaction mixture contains large amounts of hydrochloric acid and is therefore highly corrosive. The solvent methanol reacts with the hydrochloric acid forming the gas chloromethane which is toxic and needs to be separated. Consequently the process described is disadvantageous from the economic, environmental and safety standpoint.
The low selectivity to the desired product and the formation of different side products makes the economic isolation of the compound according to formula (III) not acceptable at an industrial scale.
The described prior art process(es) are therefore not suitable for a large scale production. In contrast, the new process of the present invention, as described in detail hereinafter, provides an economic process with significantly reduced formation of unwanted side-products, particularly with reduced formation of unwanted dehalogenated side-products, and remarkably increased yield of the desired reaction products.
The chemoselective catalytic hydrogenation of substituted cyanopyridines according to formula (II) as disclosed below wherein at least one of the X substituents is halogen is in general problematic. Such compounds are easily dehalogenated during the catalytic hydrogenation thus forming undesired dehalogenated side-products.
A respective of substituted cyanopyridine derivative according to formula (II), wherein at least one X substituent is halogen, preferably chlorine, can be defined by the following formula (II′) below. Upon dehalogenation during the catalytic hydrogenation process, the corresponding dehalogenated compounds of formula (II″), as defined below, can be formed.
Halogen substituted compoundcorresponding dehalogenated compound(preferably chlorine substituted compound)(preferably dechlorinated compound)(II′)(II″) p = 1, 2, 3 or 4p = 1, 2, 3 or 4each substituent X is chosen, independently of theeach substituent X is chosen, independently of theothers, as being hydrogen, halogen, C1-C4 alkyl orothers, as being hydrogen, halogen, C1-C4 alkyl orC1-C4 haloalkyl with the proviso that at least oneC1-C4 haloalkyl with the proviso that the at leastsubstituent X is halogen, preferably chlorineone halogen substituent, preferably chlorinesubstituent, of the corresponding compound (II′)is replaced by hydrogen